Synthesis of 2,6-dinitro-4,8,9,10-tetraaza-4,8,9,10-tetra-substituted adamantanes

ABSTRACT

The present invention relates to methods for synthesizing energetic compounds and intermediates thereof. Specifically, the present invention relates to methods for synthesizing adamantanes and intermediates that are useful in such synthesis. Synthesized intermediates are useful in the synthesis of bicyclic and tricyclic substituted adamantanes. Examples of various intermediates are: acyclic 2-nitromalonaldehyde intermediates, 2,6,9-tri-substituted-4,8-dinitro-2,6,9-triazabicyclo[3.3.1]nona-3,7-dienes and 2,6-dinitro-4,8,9,10-tetra-aza-4,8,9,10-tetra-substituted adamantanes. Intermediates synthesized according to the methods of the present invention are useful toward the synthesis of tetraaza-adamantanes, which can serve as precursors to potentially superior new high-energy-density compounds (HEDCs).

STATEMENT OF GOVERNMENT INTEREST

The invention described herein may be manufactured and used by or forthe Government of the United States of America for governmental purposeswithout the payment of any royalties thereon or therefore.

FIELD OF INVENTION

The present invention relates to methods for synthesizing energeticcompounds and intermediates thereof. Specifically, the present inventionrelates to methods for synthesizing adamantanes and intermediates thatare useful in such synthesis.

BACKGROUND OF THE INVENTION

Organic explosives typically consist of a carbon core and incorporatecovalently bonded oxidizer groups such as nitro, nitramine, etc. N—N andN—O bonds contained in such compounds can contribute to a positive heatof formation.

Adamantanes are C₁₀H₁₆ alicyclic hydrocarbons whose structure has thesame arrangement of carbon atoms as does the basic unit of the diamondlattice. Adamantane was first synthesized in 1941 by V. Prelog fromMeerwein's ester. Adamantanes have highly rigid skeletons with coresthat exhibit very little strain and thus exhibit high thermal stability.However, steric considerations have hampered the synthesis of stable,more energetic substituted adamantanes.

Accordingly, there is a need for intermediates and synthetic methods formaking substituted adamantanes. Specifically, synthetic methods thatenable substitution of some of the framework carbon atoms by nitrogenatoms are important because adjusting the carbon and nitrogen atomcounts may be desirable for attaining optimum explosive properties.

SUMMARY OF THE INVENTION

The following presents a simplified summary in order to provide a basicunderstanding of some aspects of the claimed subject matter. Thissummary is not an extensive overview, and is not intended to identifykey/critical elements or to delineate the scope of the claimed subjectmatter. Its purpose is to present some concepts in a simplified form asa prelude to the more detailed description that is presented later.

In one exemplary embodiment, a tricyclic intermediate compound isdescribed having a structure of Formula III:

wherein each R represents any suitable organic moiety that does notrender the compound unstable; or a pharmaceutically acceptable salt orsolvate thereof.

In various embodiments, the tricyclic intermediate compound may be anyof the following representative compounds:2,6-dinitro-4,8,9,10-tetraaza-4,8,9,10-tetrabenzyl-adamantane;2,6-dinitro-4,8,9,10-tetraaza-4,8,9,10-tetra(4-methoxybenzyl)-adamantane;2,6-dinitro-4,8,9,10-tetraaza-4,8,9,10-tetraacetyl-adamantane;2,4,6,8,9,10-hexanitro-4,8,9,10-tetraaza-adamantane;2,6-dinitro-4,8,9,10-tetraaza-4,8,9,10-tetraformyl-adamantane;2,6-dinitro-4,8,9,10-tetraaza-4,8,9,10-tetraallyl-adamantane;2,6-dinitro-4,8,9,10-tetraaza-4,8,9,10-tetracarboethoxyl-adamantane; ora pharmaceutically acceptable salt or solvate thereof.

In another embodiment, a method is described for preparing a tricyclicintermediate compound comprising reacting sodium nitromalonaldehydemonohydrate with a substituted amine to form at least one tricyclicintermediate. In further embodiments, the substituted amine is a primaryalkylamine or primary arylamine. Alternatively, the substituted aminecan be benzylamine or allylamine.

In an alternative embodiment, a method is described for preparing atricyclic intermediate compound comprising reacting a bicyclicintermediate compound having a structure of Formula II:

with a substituted amine to form at least one tricyclic intermediate. Infurther embodiments, the substituted amine is a primary alkylamine orprimary arylamine. Alternatively, the substituted amine can bebenzylamine or allylamine.

Other aspects of the invention are found throughout the specification.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to methods for synthesizing energeticcompounds and intermediates thereof. Specifically, the present inventionrelates to methods for synthesizing adamantanes and intermediates thatare useful in such synthesis.

When the terms “one,” “a,” or “an” are used in this disclosure, theymean “at least one” or “one or more,” unless otherwise indicated.

The disclosure that follows will refer generally to three types ofgeneric structures as follows:

Formula I represents the structure of acyclic 2-nitromalonaldehydeintermediates that are useful in the synthesis of bicyclic compounds,which in turn are useful as intermediates in the synthesis of tricyclicsubstituted adamantanes. As used herein, the term “acyclic” refers tothe core structure, and not to the R group, which may or may not beacyclic.

Formula II represents the structure of the bicyclic compounds:2,6,9-tri-substituted-4,8-dinitro-2,6,9-triazabicyclo[3.3.1]nona-3,7-dienes.As stated above, such compounds are useful as intermediates in thesynthesis of tricyclic substituted adamantanes.

Formula III represents the structure of the tricyclic substitutedadamantanes: 2,6-dinitro-4,8,9,10-tetraaza-4,8,9,10-tetra-substitutedadamantanes.

Acyclic Intermediates

The acyclic intermediates according to Formula I are synthesized, forexample, from sodium nitromalonaldehyde monohydrate and an appropriatesubstituted amine, and in an exemplary embodiment, containing a groupremovable later by chemical means, such as benzylamine or allylamine.

The acid-catalyzed condensation of sodium nitromalonaldehyde monohydratewith primary alkylamines and primary arylamines generally occursstepwise, to form nitroenamines as products also containing an imine orSchiff base functionality. In the first step of the condensation, theamine and aldehyde give rise to an aminal, which is dehydrated underacidic conditions to afford the corresponding Schiff base (imine).Depending upon the nature of the primary amine, the reaction solvent(s)and the acidity strength of the catalyst (e.g. formic acid), the acycliccompounds represented by Formula I can be formed as the major products.

In the practice of the present invention, R may be any suitable organicmoiety that does not render the compound unstable. Exemplary R groupsinclude, for example, the following: benzyl, alkoxybenzyl, acetyl,nitro, formyl, allyl and carboalkoxyl.

The following compounds are representative acyclic intermediates:

Acyclic Intermediate 1 (I1): Bis(N-benzylimino)-2-nitromalonaldehyde(CAS Name: Benzenemethanamine,N-[2-nitro-3-[(phenylmethyl)amino]-2-propen-1-ylidene]-)

Acyclic Intermediate 2 (I2): Bis[N-(4-methoxybenzylimine)] of2-nitromalonaldehyde (CAS Name: (4-Methoxyphenyl)methanamine,N-[2-nitro-3-[(4-methoxyphenylmethyl)amino]-2-propen-1-ylidene]-)

Acyclic Intermediate 3 (I3): Bis(N-acetylimine) of 2-nitromalonaldehyde(CAS Name: Acetamide, N-[2-nitro-3-[(acetypamino]-2-propen-1-ylidene]-)

Acyclic Intermediate 4 (I4): Bis(N-nitroimine) of 2-nitromalonaldehyde

Acyclic Intermediate 5 (I5) Bis(N-formylimine) of 2-nitromalonaldehyde(CAS Name: Formamide, N-[2-nitro-3-[(formyl)amino]-2-propen-1-ylidene]-)

Acyclic Intermediate 6 (I6): Bis(N-allylimine) of 2-nitromalonaldehyde

Acyclic Intermediate 7 (I7): Bis(N-carboethoxylimine) of2-nitromalonaldehyde

Bicyclic Compounds

The acyclic intermediates just described are useful in the synthesis ofbicyclic compounds (BCs) that are useful as intermediates in thesynthesis of tricyclic compounds (TCs). Depending upon the nature of theprimary amine, the reaction solvent(s) and the acidity strength of thecatalyst (e.g. formic acid), the bicyclic compounds represented byFormula II can be formed as the major products and under certainreaction conditions, the tricyclic compounds represented by Formula IIIcan be detected in the crude reaction mixture. Synthesis of the bicycliccompounds generally involves reacting sodium nitromalonaldehydemonohydrate with the appropriate substituted amine or by reaction of theacyclic intermediate represented by Formula I with the appropriatesubstituted amine as described in greater detail in the Examplessection. Reaction conditions can be determined using routineoptimization.

The following compounds are representative bicyclic intermediates:

Bicyclic Intermediate 1 (BC1):2,6,9-Tribenzyl-4,8-dinitro-2,6,9-triazabicyclo[3.3.1]nona-3,7-diene

Bicyclic Intermediate 2 (BC2):2,6,9-Tri(4-methoxybenzyl)-4,8-dinitro-2,6,9-triazabicyclo[3.3.1]nona-3,7-diene

Bicyclic Intermediate 3 (BC3):2,6,9-Triacetyl-4,8-dinitro-2,6,9-triaza-bicyclo[3.3.1]nona-3,7-diene

Bicyclic Intermediate 4 (BC4):2,4,6,8,9-Pentanitro-2,6,9-triaza-bicyclo[3.3.1]nona-3,7-diene

Bicyclic Intermediate 5 (BC5):2,6,9-Triformyl-4,8-dinitro-2,6,9-triaza-bicyclo[3.3.1]nona-3,7-diene

Bicyclic Intermediate 6 (BC6):2,6,9-Triallyl-4,8-dinitro-2,6,9-triaza-bicyclo[3.3.1]nona-3,7-diene

Bicyclic Intermediate 7 (BC7):2,6,9-Tricarboethoxyl-4,8-dinitro-2,6,9-triaza-bicyclo[3.3.1]nona-3,7-diene

Tricyclic Compounds

Again, depending upon the nature of the primary amine, the reactionsolvent(s) and the acidity strength of the catalyst (e.g. formic acid),the bicyclic compounds represented by Formula H can be formed as themajor products and under certain reaction conditions, the tricycliccompounds represented by Formula III can be detected in the crudereaction mixture.

The following compounds are representative tricyclic compounds:

Tricyclic Compound 1 (TC1):2,6-dinitro-4,8,9,10-tetraaza-4,8,9,10-tetrabenzyl-adamantane

Tricyclic Compound 2 (TC2):2,6-dinitro-4,8,9,10-tetraaza-4,8,9,10-tetra(4-methoxybenzyl)-adamantane(also may be referred to as “4-MeOBn-TC”)

Tricyclic Compound 3 (TC3):2,6-dinitro-4,8,9,10-tetraaza-4,8,9,10-tetraacetyl-adamantane (also maybe referred to as “Ac-TC”)

Tricyclic Compound 4 (TC4):2,4,6,8,9,10-hexanitro-4,8,9,10-tetraaza-adamantane (also may bereferred to as “NO₂-TC”)

Tricyclic Compound 5 (TC5):2,6-dinitro-4,8,9,10-tetraaza-4,8,9,10-tetraformyl-adamantane (also maybe referred to as “HCO-TC”)

Tricyclic Compound 6 (TC6):2,6-dinitro-4,8,9,10-tetraaza-4,8,9,10-tetraallyl-adamantane (also maybe referred to as “Allyl-TC”)

Tricyclic Compound 7 (TC7):2,6-dinitro-4,8,9,10-tetraaza-4,8,9,10-tetracarboethoxyl-adamantane(also may be referred to as “EtOCO-TC”)

Uses

The intermediates disclosed above are useful toward the synthesis oftetraaza-adamantanes, which can serve as precursors to superior newhigh-energy-density compounds (HEDCs), also referred to as “organic cagecompounds”, such as polynitrotetraaza-adamantanes. These compounds havesuperior energetic properties, due to their higher calculated densitiesand high calculated performance parameters (e.g. detonation properties).

The tetraazaadamantanes disclosed above are expected to be keyprecursors which, after protecting group removal by eitherhydrogenolysis, nitrolysis or other chemical means, and subsequentpolynitration could afford novel, high-performance HEDCs includinghexanitro- and octanitro-tetraazaadamantanes, and may provide potentialpharmaceutical uses and benefits.

EXAMPLES Actual

Methods for synthesizing representative intermediates are described inthis section. All intermediates described herein but not specificallymentioned below, can be synthesized by varying the below methods usingwell known organic chemical synthesis techniques.

Example 1 Compound I1

Compound I1 can be represented by Formula IV as follows:

As depicted, “Ph” is an unsubstituted phenyl moiety.

Synthesis of (3E)-N-((E)-3-(benzylimino)-2-nitropropylidene)(phenyl)methanamine (Compound I1)

A turbid, yellow-orange solution of sodium nitromalonaldehydemonohydrate (15.7 mg, 0.10 mmol) in DMF (275 uL) and water (25 uL) wasadded dropwise over a 2 min period to a solution of benzylamine (27.4uL, 0.25 mmol) in DMF (165 uL), water (15 uL) and 96% formic acid (0.94uL, 0.025 mmol) and was stirred at room-temperature for 24 h. A fewdrops of the reaction mixture were added to ˜1 mL water giving a white,opaque emulsion that was extracted with EtOAc twice. The combinedorganics were dried over Na₂SO₄, evaporated under N₂ and dried in vacuoat room-temperature to give 3.0 mg of the crude title compound (I1) as apale-pink residue (3.0 mg, 10% crude yield); HRMS calcd for C₁₇H₁₈N₃O₂(M+H⁺) 296.13990, obsd 296.13733 (100%); ¹H NMR (300 MHz, DMSO-d₆) δ4.719 (s, 4H), 7.274-7.304 (m, 10H), 8.898 (s, 2H), ˜11.7 (br s, 1H).

Example 2 Compound I2

Compound I2 can be represented by Formula V as follows:

Synthesis of(3E)-N-((E)-3-(4-methoxybenzylimino)-2-nitropropylidene)(4-methoxyphenyl)methanamine(I2)

A yellow-orange suspension of sodium nitromalonaldehyde monohydrate(15.7 mg, 0.10 mmol) in methanol (275 uL) and water (25 uL) was addeddropwise over a 2 min period to a solution of 4-methoxybenzylamine inmethanol (165 uL), water (15 uL) and 96% formic acid (0.83 uL, 0.022mmol) and was stirred at room-temperature for 24 h. It was noted thatduring the NMA addition a precipitate started to crystallize out, andwas analyzed and found to be the crude title compound (I2). Filtrationgave a pale-yellow powder (14.5 mg, 41% crude yield) that wasrecrystallized from a minimum volume of absolute ethanol (˜0.75 mL)yielding 13 mg (37%) of the title compound as pale-yellow,microcrystalline flakes: mp 131.5-132° C.; HRMS calcd for C₁₉H₂₂N₃O₄(M+H⁺) 356.1610, obsd 356.15571; NMR (300 MHz, DMSO-d₆) δ 3.737 (s, 6H),4.621 (s, 4H), 6.891, 6.885, 6.869, 6.862 (dd, 4H), 7.196-7.167 (d, 4H),8.840 (s, 2H), ˜11.7 (br s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 145.704,135.410, 135.380, 128.787, 128.382, 128.199, 127.879, 127.230, 120.561,64.383, 57.309, 52.166; Anal. Calcd for C₁₉H₂₁N₃O₄ (355.39): C, 64.21;H, 5.96; N, 11.82. Found: C, 64.04; H, 5.96; N, 11.86.

Example 3 Compound BC1

Compound BC1 can be represented by Formula VI as follows:

As depicted, “Bn” is an unsubstituted benzyl moiety.

Synthesis of2,6,9-Tribenzyl-4,8-dinitro-2,6,9-triaza-bicyclo[3.3.1]nona-3,7-diene(BC1)

A yellow-orange suspension of sodium nitromalonaldehyde monohydrate (63mg, 0.40 mmol) in methanol (760 uL), water (32 uL) and 96% formic acid(3.2 uL, 0.084 mmol) was stirred at room-temperature and benzylamine(91.7 uL, 0.84 mmol) was added dropwise over a 5 min period during whichthe reaction solids dissolved, subsequently the crude product thenquickly crystallized. The orange reaction mixture was stirred about 2days at room-temperature. Filtration gave a yellow powder (63 mg) ofwhich 59 mg was recrystallized from absolute ethanol (˜10 mL) yielding25 mg (26%) of the title compound BC1 as a yellow, microcrystallinesolid: mp 184-185° C.; FIRMS calcd for C₂₇H₂₆N₅O₄ (M+H⁺) 484.1985, obsd484.18924; ¹H NMR (300 MHz, DMSO-d₆) δ 3.004 (s, 2H), 4.789-5.002 (q,4H), 5.350 (s, 2H), 6.631-6.659 (d, 2H), 7.035-7.136 (m, 3H), 7.36-7.37(br s, 10H), 8.800 (s, 2H); ¹H NMR (300 MHz, CDCl₃) δ 2.948, 2.955 (d,2H), 4.581, 4.630 (d, 2H), 4.974, 5.023 (d, 2H), 5.308 (s, 2H), 6.714,6.737 (d, 2H), 7.090, 7.116, 7.170-7.20 (m, 3H), 7.289, 7.298, 7.310,7.321, 7.335, 7.342, 7.353, 7.363, 7.375 (complex m, 10H), 8.358 (s,2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 145.704, 135.410, 135.380, 128.787,128.382, 128.199, 127.879, 127.230, 120.561, 64.383, 57.309, 52.166;Anal. Calcd for C₂₇H₂₅N₅O₄ (483.52): C, 67.07; H, 5.21; N, 14.48. Found:C, 66.80; H, 5.13; N, 14.45.

Example 4 Compound BC6

Compound BC6 can be represented by Formula VII as follows:

Synthesis of2,6,9-Triallyl-4,8-dinitro-2,6,9-triaza-bicyclo[3.3.1]nona-3,7-diene(BC6)

A yellow-orange suspension of sodium nitromalonaldehyde monohydrate(63.5 mg, 0.404 mmol) in 8.3% aq. methanol (1:11 v/v) solution (1200uL), was mixed with a solution of 96% formic acid (3.9 uL, 0.100 mmol)in 8.3% aq. methanol solution (720 uL), and was stirred for severalminutes at room-temperature. Allylamine (76 uL, 1.00 mmol) was addeddropwise (˜40 drops) over a ˜20 sec period during which the reactionsolids dissolved. The crude reaction mixture was stirred atroom-temperature overnight. TLC (EtOAc:hexane {1:2 v/v}) showed ayellow, major spot for desired product at R_(f)=0.30 (UV) with at leasttwo other minor spots at R_(f)=0.37 and 0.24 (UV). Reaction solvent andvolatiles were evaporated in vacuo at 30° C. to give an orange-redsemi-solid that was partitioned between EtOAc and water renderedalkaline with a minimum amount of satd. NaHCO₃. The aqueous layer wasseparated, extracted with EtOAc (3×), the combined organics were driedover Na₂SO₄ and concentrated in vacuo giving a dark red oil (41 mg).Flash chromatography on silica and elution with 0-0.5% MeOH:CH₂Cl₂ gavethree components that were isolated and characterized. After evaporationof selected fractions, a yellow oil (14 mg, 21% yield) was confirmed asthe major component by weight, and identified as desired product BC6having spectra consistent with structure, confirmed by HRMS (DART _Pos)analysis which detected the product ion (M+H⁺) 334.12210 (A ˜23K) and ¹HNMR (300 MHz, CDCl₃ nt=16) δ 8.208 (s, 2H), 5.89-5.74 (m, 3H),5.491-5.205 (m, 8H), 4.475, 4.450, 4.425, 4.400 (dd, 2H), 4.166, 4.162,4.149, 4.145, 4.116, 4.112, 4.103, 4.098, dd, dd, 2H), 3.058, 3.038,3.034, 3.012, 3.009, 2.993, 2.989, 2.946, 2.943, 2.924, 2.901, 2.879(ddq, 2H). ¹H NMR {of a prior preparative TLC (EtOAc:hexane {1:2 v/v})purified sample, pumped in vacuo at 65° C. to give 0.4 mg} (300 MHz,DMSO-d₆ nt=512) δ 8.495 (s, 2H), 6.0-5.8 (m, 4H), 5.8-5.7 (m, 1H),5.432, 5.392, 5.387, 5.335, 5.330, 5.307, 5.303, 5.273, 5.269, 5.182(dd, dd, dd, dd, 8H), 4.339, 4.321, 4.298 (dt, 4H); ¹³C NMR {of theflash chromatographed pure sample, ˜14 mg} (75 MHz, CDCl₃ nt=30720) δ144.387, 132.334, 131.495, 121.581, 121.483, 120.701, 65.819, 57.541,52.798; FIRMS (DART, flash purified sample) calcd for C₁₅H₂₀N₅O₄ (M+H⁺)334.1515, obsd 334.12210.

Example 5 Compound TC1

A tricyclic compound is synthesized from BC1 using known organicsynthesis techniques. Compound TC1 can be represented by Formula VII asfollows, where “Bn” represents an unsubstituted benzyl moiety:

Synthesis of2,6-Dinitro-4,8,9,10-tetraaza-4,8,9,10-tetrabenzyladamantane (TC1)

A suspension of2,6,9-tribenzyl-4,8-dinitro-2,6,9-triaza-bicyclo[3.3.1]nona-3,7-diene(BC1) (8.0 mg, 0.0166 mmol) in 4% aq. CH₃CN (500 uL) was treated with91% formic acid (1.0 uL, 0.024 mmol) catalyst, and benzylamine (˜2.2 uL,0.020 mmol) was added at room-temperature. The reaction mixture wasimmersed in a hot (81° C.) oil bath and soon changed to a solution, andwas heated for 2.5 h. Analysis of the crude reaction mixture by FIRMSdetected the intended product ion (M+H⁺) 591.30675 (A ˜2.3K); calcd forC₃₄H₃₅N₆O₄ (M+H⁺) 591.27198. Expansion showed an ion (M+1)H⁺592.34379and ion (M+2)H⁺593.36871. The major component of the reaction productsmixture was unreacted BC1 which was confirmed by HRMS, calcd forC₂₇H₂₆N₅O₄ (M+H⁺) 484.1985, obsd 484.19637 (A ˜72K); and ¹H NMR (300MHz, DMSO-d₆) was consistent with structure for BC1 (25H).

Finally, any numerical parameters set forth in the specification andattached claims are approximations (for example, by using the term“about”) that may vary depending upon the desired properties sought tobe obtained by the present invention. At the very least, and not as anattempt to limit the application of the doctrine of equivalents to thescope of the claims, each numerical parameter should at least beconstrued in light of the number of significant digits and by applyingordinary rounding.

What is claimed is:
 1. A tricyclic intermediate compound having astructure of Formula III:

wherein each R is an unsubstituted benzyl moiety.
 2. The tricyclicintermediate compound according to claim 1, wherein the tricyclicintermediate compound is a2,6-dinitro-4,8,9,10-tetraaza-4,8,9,10-tetrabenzyl-adamantane.
 3. Amethod for preparing a tricyclic intermediate compound, comprising:reacting a bicyclic intermediate compound having a structure of FormulaII:

with a substituted amine to form at least one tricyclic intermediatecompound, wherein R is an unsubstituted benzyl moiety.
 4. The methodaccording to claim 3, wherein the substituted amine is a benzylamine.